Chimeric Antigen Receptor T CellsDirected Against CD19 Induce Durable Responses and Transient Cytokine Release Syndrome in Relapsed, Refractory CLL and ALL

Porter DL et al.Proc ASH 2012;Abstract 717.

Background

Chimeric antigen receptors (CARs) combine the antigen recognition domain of an antibody with intracellular signaling domains into a single chimeric protein.

CD19 is an ideal target for CARs because expression is restricted to normal and malignant B cells.

With relatively short follow-up, initial data on antitumor activity of CAR-modified autologous T cells targeted to CD19 (CART19 cells) were reported for 3 patients with CLL (NEJM 2011;365:725; Sci Transl Med 2011;3:95ra73).

Study objective: Present updated outcomes and longer follow-up analyses from 10 patients with relapsed/refractory CLL or ALL treated with CART19 cells.

Porter DL et al. Proc ASH 2012;Abstract 717.

Treatment of Patients with CART19 Cells

With permission from Porter DL et al. Proc ASH 2012;Abstract 717.

Autologous T cells collected by leuka-pheresis were transduced with a lentivirus encoding the anti-CD19 scFv linked to the 4-1BB (CD137) and CD3-z signaling domains.

Gene-modified T cells were expanded and activated ex vivo by exposure to anti-CD3/CD28 beads.

Ten patients received T-cell infusions con-taining a proportion of CART19 cells.

Patients with CLL received lymphodepleting chemotherapy 4 to 7 days prior to infusion.

Patients with ALL experienced chemo-refractory relapse, received 6 weeks of chemotherapy prior to infusion and did not require further lymphodepletion.

CAR

CD28Y

ZAP70

CD28

Y

ZAP70

Signalingdomains

Anti-CD19 ligand binding

domain scFv

aVH

V LVL

VH

Study Design and Eligibility

Single-center pilot trial of CTL019 (formally CART19) cells

Primary objective:

– Safety, feasibility and immunogenicity of CTL019 in patients with CD19-positive leukemia and lymphoma

Eligibility:

– CD19-positive B-cell malignancies with no available curative options (such as autologous or allogeneic stem cell transplant)

– Failed ≥2 prior therapies, progression within 2 years of last treatment

– Limited prognosis (<2 years) with available therapies

Porter DL et al. Proc ASH 2012;Abstract 717.

Clinical Response

Porter DL et al. Proc ASH 2012;Abstract 717.

Pt UPN# Blood Marrow Nodes Expansion Comments Max resp

01 NED NED NED >3 log MRD* neg CR 28 mo+

02 NED NED NED >3 log MRD* neg CR 27 mo+

03 PR PR PR 2 log PR 4 mo

04 PR PR PR 2 log PR 4 mo

05 NR NR NR <2 log NR

06 NR NR NR <2 log NR

09 NED NED NED >3 log MRD* neg CR 7 mo+

10 NED NED PR 2 log Bulky nodes PR 3 mo+

12 NED NED PR 2 log Bulky nodes PR 2 mo+

14 ne ne ne ne

* MRD assessed with deep sequencing analysis

NED = no evidence of disease; MRD = minimal residual disease; CR = complete response; PR = partial response; ne = not evaluated

Marrow Response Observed in Patient UPN02

With permission from Porter DL et al. Proc ASH 2012;Abstract 717.

Pre-infusions marrow:>50% involved by CLL (40x)

Day 31No evidence CLL and negative

by flow cytometry, cytogenetics, FISH or deep sequencing

CT Response Observed in Patient UPN02

With permission from Porter DL et al. Proc ASH 2012;Abstract 717.

Response sustained >24 mo after CART-19 cell infusion

Toxicity Summary of CTL019 (CART19)

Porter DL et al. Proc ASH 2012;Abstract 717.

No significant infusional toxicity Hepatotoxicity (Grade 3-4 in 5 responding patients) Renal toxicity (Grade 3 in 1 patient)

– Related to tumor lysis syndrome, acute tubular necrosis from hypotension

– Reversible B-cell aplasia and hypogammaglobulinemia in patients

achieving complete response– Treated with intravenous immunoglobulin– No excessive or frequent infections

Tumor lysis syndrome Cytokine release syndrome

CTL019 (CART19)-Associated Cytokine Release Syndrome (CRS)

Porter DL et al. Proc ASH 2012;Abstract 717.

All responding patients developed a CRS at time of T-cell expansion

– High fevers, nausea, hypotension, hypoxia, etc

Associated with high levels of:

– IL-6 (6-400x)

– IFN-gamma (89-1,000)

– IL-2R (5-25)

– No significant increase in TNF-alpha, IL-2

Immediately reversed with steroids (n = 1), steroids/etanercept/tocilizumab (n = 1), tocilizumab (n = 2)

Author Conclusions

Autologous T cells genetically engineered to express an anti-CD19 scFv coupled to 4-1BB/CD3-z signaling domains can undergo robust in vivo expansion and persist for more than 2 years.

CART19 cells can induce an overall response rate of 78%.

– 3/9 complete and 4/9 partial responses, including CR in 2/2 patients with ALL

Responding patients develop cytokine release syndrome, which can be treated effectively with anticytokine therapy.

Porter DL et al. Proc ASH 2012;Abstract 717.

Investigator Commentary — CAR T Cells Directed Against CD19 Induce Durable Responses and Transient CRS in Relapsed, Refractory CLL and ALL

CAR-targeted therapy is designed for patients with cancer that expresses CD19. Most of the patients enrolled on this study have refractory CLL. Patients’ T cells are harvested and genetically modified with a vector that will express a receptor that targets CD19. The cells are then infused back into the patient. It’s a time-consuming and expensive procedure, but it definitely has merit. The authors have reported about 6 objective responses to date, some of which are CRs and are durable. This is a highly attractive strategy for ALL because once a patient experiences relapse we have no effective agents against this disease. I believe this strategy deserves more development in ALL. However, the challenge for this strategy in CLL is that we have some novel, easier-to-use and active agents — ibrutinib, ABT-199 — coming down the road. A few years ago this might have been the hottest strategy out there, but the field has changed so much that I’m a little skeptical that this therapy will make it to prime time in CLL.

Interview with Brad S Kahl, MD, January 17, 2013